PET IMAGING STUDY OF BRAIN VMAT2 IN HUMAN METHAMPHETAMINE USERS OBJECTIVE. Our broad goal is to obtain brain imaging data in human methamphetamine (MA) users that could help in development of the vesicular monoamine transporter (VMAT2) as a biomarker to explain pathophysiology and guide clinicians to more appropriate treatment interventions in the drug users. VMAT2 is the synaptic vesicle transporter responsible for monoamine neurotransmitter packaging in human brain, is predominantly localized to dopaminergic terminals in human striatum, and is now proposed in this application as a new tool to investigate vesicular dopamine status in psychostimulant users. BACKGROUND. At present there exists no useful treatment for addiction to the stimulant MA. Although controversial, we believe that a brain deficiency of the neurotransmitter dopamine, as suggested by our postmortem brain findings, might be responsible for some of the behavioural (especially cognitive) problems of MA users. However, in vivo data suggesting dopamine deficiency in MA users are lacking. In a pilot positron emission tomography (PET) study of MA users we discovered, unexpectedly, that striatal (+)- [11C]DTBZ binding to VMAT2 was increased during early abstinence, a finding which can be explained by decreased competition between dopamine (reduced in some MA users) and (+)-[11C]DTBZ binding to VMAT2. As an in vivo biomarker of vesicular dopamine status might be helpful in selecting the most appropriate treatment for MA users, there is need to confirm these findings in a representative number of subjects and establish in a longitudinal study whether binding levels do or do not decline in early abstinence. SPECIFIC AIM, DESIGN, AND HYPOTHESIS. Our major SPECIFIC AIM is to measure by PET imaging striatal (+)-[11C]DTBZ binding in a representative number of chronic MA users, with each user assessed at 4-7, 12-15, and 28-30 days following last use of the drug, and in a matched control group. Based on our pilot data, our major working HYPOTHESIS is that striatal (+)-[11C]DTBZ binding will be above normal in MA users during very early abstinence (4-7 days) and that levels might normalize in later abstinence (30 days). SIGNIFICANCE. Our study, designed and executed by investigators with extensive VMAT2 expertise in both the human and experimental animal, is a first step aimed at developing a brain biomarker that might identify those MA users who could receive benefit from dopamine substitution medication. In addition, the findings could provide unique information that could help interpretation of brain imaging VMAT2 data in neurology applications for which this biomarker has been proposed to assess efficacy of neuroprotective agents.